Quinoline derivatives and their use as antibacterial agents

ABSTRACT

Piperidine derivatives and pharmaceutical derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.

This application is a 371 of PCT/EP99/07766, filed on Oct. 11, 1999.

This invention relates to novel medicaments, being novel antibacterialcompounds and compositions.

JP04095071 discloses piperidyl carbamic acid derivatives for treatingdementia by ameliorating memory disturbance.

This invention provides a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof:

wherein:

one of Z¹, Z², Z³, Z⁴ and Z⁵ is N or CR^(1a) and the remainder are CH;

R¹ is selected from hydroxy; (C₁₋₆)alkoxy optionally substituted by(C₁₋₆)alkoxy, amino, piperidyl, guanidino or amidino optionallyN-substituted by one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonylgroups, NH₂CO, hydroxy, thiol, (C₁₋₆)alkylthio, heterocyclylthio,heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkoxy-substituted (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; nitro; trifluoromethyl; azido; acyl;acyloxy; acylthio; (C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide;arylsulphonyl; arylsulphoxide or an amino, piperidyl, guanidino oramidino group optionally N-substituted by one or two (C₁₋₆)alkyl, acylor (C₁₋₆)alkylsulphonyl groups, or when one of Z¹, Z², Z³, Z⁴ and Z⁵ isN, R¹ may instead be hydrogen;

R^(1a) is selected from hydrogen and the groups listed above for R¹;

either R² is hydrogen; and

R³ is in the 2- or 3-position and is hydrogen or (C₁₋₆)alkyl or(C₂₋₆)alkenyl optionally substituted with 1 to 3 groups selected from:

thiol; halogen; (C₁₋₆)alkylthio; trifluoromethyl; azido;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;(C₂₋₆)alkenylcarbonyl; hydroxy optionally substituted by (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl or aminocarbonyl whereinthe amino group is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; amino optionally mono- ordisubstituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonyl wherein the amino group isoptionally mono- or disubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl; oxo; (C₁₋₆)alkylsulphonyl;(C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl;

or when R³ is in the 2-position it may with R⁴ form a C₃₋₅ alkylenegroup optionally substituted by a group R⁵ selected from:

(C₃₋₁₂)alkyl; hydroxy(C₃₋₁₂)alkyl; (C₁₋₁₂)alkoxy(C₃₋₁₂)alkyl;(C₁₋₁₂)alkanoyloxy(C₃₋₁₂)alkyl; (C₃₋₆)cycloalkyl(C₃₋₁₂)alkyl; hydroxy-,(C₁₋₁₂)alkoxy- or (C₁₋₁₂)alkanoyloxy-(C₃₋₆)cycloalkyl(C₃₋₁₂)alkyl;cyano(C₃₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; tetrahydrofuryl;mono- or di-(C₁₋₁₂)alkylamino(C₃₋₁₂)alkyl; acylamino(C₃₋₁₂)alkyl;(C₁₋₁₂)alkyl- or acyl-aminocarbonyl(C₃₋₁₂)alkyl; mono- ordi-(C₁₋₁₂)alkylamino(hydroxy)(C₃₋₁₂)alkyl; optionally substitutedphenyl(C₁₋₂)alkyl, phenoxy(C₁₋₁₂)alkyl or phenyl(hydroxy)(C₁₋₂)alkyl;optionally substituted diphenyl(C₁₋₂)alkyl; optionally substitutedphenyl(C₂₋₃)alkenyl; optionally substituted benzoyl or benzoylmethyl;optionally substituted heteroaryl(C₁₋₂)alkyl; and optionally substitutedheteroaroyl or heteroaroylmethyl;

or R³ is in the 3-position and R² and R³ together are a divalent residue═CR⁵ ¹ R⁶ ¹ where R⁵ ¹ and R⁶ ¹ are independently selected from H,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, aryl(C₁₋₆)alkyl and aryl(C₂₋₆)alkenyl, anyalkyl or alkenyl moiety being optionally substituted by 1 to 3 groupsselected from those listed above for substituents on R³;

R⁴ forms a group with R³ as above defined or is a group —CH₂—R⁵ in whichR⁵ is as defined above:

n is 0, 1 or 2; and

A is NHC(O)NH or NHC(O)O.

In one aspect the invention provides compounds of formula (I) where R1and R1a are selected from the groups listed above other thantrifluoromethyl.

The invention also provides a method of treatment of bacterialinfections in mammals, particularly in man, which method comprises theadministration to a mammal in need of such treatment of an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablederivative thereof.

The invention also provides the use of a compound of formula (I) or apharmaceutically acceptable derivative thereof in the manufacture of amedicament for use in the treatment of bacterial infections in mammals.

The invention also provides a pharmaceutical composition for use in thetreatment of bacterial infections in mammals comprising a compound offormula (I), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier.

Preferably Z¹-Z⁵ are each CH or Z¹ is N and Z²-Z⁵ are each CH.

When R¹ or R^(1a) is substituted alkoxy it is preferably (C₁₋₆)alkoxysubstituted by optionally N-substituted amino, piperidyl, guanidino oramidino, more preferably by amino or guanidino. Suitable examples of R¹alkoxy include methoxy, n-propyloxy, i-butyloxy, aminoethyloxy,aminopropyloxy, aminopentyloxy, guanidinopropyloxy,piperidin-4-ylmethyloxy, phthalimido pentyloxy or2-aminocarbonylprop-2-oxy. Preferably R¹ is methoxy,amino(C₃₋₅)alkyloxy, guanidino(C₃₋₅)alkyloxy, nitro or fluoro, mostpreferably methoxy.

Preferably R^(1a) is hydrogen.

Preferably n is 0.

Preferably A is NHCONH.

R³ is preferably hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, optionallysubstituted 1-hydroxy-(C₁₋₆)alkyl, more preferably hydroxymethyl or1,2-dihydroxy(C₂₋₆)alkyl wherein the 2-hydroxy group is optionallysubstituted. Preferred examples of R³ include hydroxymethyl,1-hydroxyethyl or 1,2-dihydroxyethyl wherein the 2-hydroxy group isoptionally substituted with alkylcarbonyl or aminocarbonyl where theamino group is optionally substituted. Other suitable examples of R³include 2-hydroxyethyl, 2- or 3-hydroxypropyl, ethyl or vinyl.

R3 is preferably in the 3-position.

When R² and R³ together form a group, this is preferably ═CHCH₃.

When R3 and R4 together form a group, this is preferably —(CH₂)₄—optionally substituted by R⁵. Preferably R⁵ on this cyclic group is(C₄₋₉)alkyl, unsubstituted phenyl(C₁₋₂)alkyl or unsubstitutedphenyl(C₂₋₃)alkenyl, more preferably n-pentyl or n-hexyl. mostpreferably n-pentyl.

Suitable groups R⁴ include n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-dodecyl, methoxybutyl, phenylethyl, phenylpropyl or3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring,3-benzoylpropyl, 4-benzoylbutyl, 3-pyridylmethyl,3-(4-fluorobenzoyl)propyl, cyclohexylmethyl, cyclobutylmethyl,t-butoxycarbonylaminomethyl and phenoxyethyl.

Preferably R⁴ is (C₅₋₁₀)alkyl, unsubstituted phenyl(C₂₋₃)alkyl orunsubstituted phenyl(C₃₋₄)alkenyl, more preferably hexyl, heptyl,5-methylhexyl, 6-methyl heptyl, 3-phenyl-prop-2-en-yl or 3-phenylpropyl,most preferably n-heptyl.

Most preferably R⁵ is unbranched at the α and, where appropriate, βpositions.

Halo or halogen includes fluoro, chloro, bromo and iodo.

The term ‘heterocyclic’ as used herein includes aromatic andnon-aromatic, single and fused, rings suitably containing up to fourhetero-atoms in each ring selected from oxygen, nitrogen and sulphur,which rings may be unsubstituted or substituted by, for example, up tothree groups selected from optionally substituted amino. halogen,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, halo(C₁₋₆)alkyl, hydroxy, carboxy, carboxysalts, carboxy esters such as (C₁₋₆)alkoxycarbonyl,(C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl, aryl, and oxo groups. Each heterocyclicring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fusedheterocyclic ring system may include carbocyclic rings and need includeonly one heterocyclic ring. Compounds within the invention containing aheterocyclyl group may occur in two or more tautometric forms dependingon the nature of the heterocyclyl group; all such tautomeric forms areincluded within the scope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include (C₁₋₁₆)alkyl optionallysubstituted by hydroxy, (C₁₋₆)alkoxy, thiol, (C₁₋₆)alkylthio, halo ortrifluoromethyl, and amino-protecting groups such as acyl or(C₁₋₆)alkylsulphonyl groups.

The term ‘heteroaryl’ includes the aromatic heterocyclic groups referredto above. Examples of heteroaryl groups include pyridyl, triazolyl,tetrazolyl, indolyl, thienyl, isoimidazolyl, thiazolyl,furanyl,quinolinyl, imidazolidinyl and benzothienyl.

When used herein the term ‘aryl’, includes phenyl and naphthyl, eachoptionally substituted with up to five, preferably up to three, groupsselected from halogen, mercapto, (C₁₋₁₆)alkyl, phenyl, (C₁₋₁₆)alkoxy,hydroxy(C₁₋₁₆)alkyl, mercapto (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy,optionally substituted amino, nitro, carboxy, (C₁₋₆)alkylcarbonyloxy,(C₁₋₁₆)alkoxycarbonyl, formyl, or (C₁₋₆)alkylcarbonyl groups.

The term ‘acyl’ includes (C₁₋₁₆)alkoxycarbonyl, formyl or(C₁₋₆)alkylcarbonyl group.

Compounds of formula (I) wherein:

R³ is hydroxy(C₁₋₆)alkyl or 1,2-dihydroxy(C₂₋₆)alkyl optionallysubstituted on the hydroxy group(s) as claimed, hereinafter ‘compoundsof formula (IA)’, are particularly preferred.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable derivativethereof, and a pharmaceutically acceptable carrier.

Some of the compounds of this invention may be crystallised orrecrystallised from solvents such as organic solvents. In such casessolvates may be formed. This invention includes within its scopestoichiometric solvates including hydrates as well as compoundscontaining variable amounts of water that may be produced by processessuch as lyophilisation.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach provided in substantially pure form, for example at least 60% pure,more suitably at least 75% pure and preferably at least 85%, especiallyat least 98% pure (% are on a weight for weight basis). Impurepreparations of the compounds may be used for preparing the more pureforms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or salt thereof.

Pharmaceutically acceptable derivatives of the above-mentioned compoundsof formula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic or sulphuric acids, or organic acids,e.g. acetic, fumaric or tartaric acids. Compounds of formula (I) mayalso be prepared as the N-oxide.

Certain of the above-mentioned compounds of formula (I) may exist in theform of optical isomers, e.g. diastereoisomers and mixtures of isomersin all ratios, e.g. racemic mixtures. The invention includes all suchforms, in particular the pure isomeric forms.

In a further aspect of the invention there is provided a process forpreparing compounds of formula (I), or a pharmaceutically acceptablederivative thereof, which process comprises reacting a compound offormula (IV) with a compound of formula (V):

wherein Z¹, Z², Z³, Z⁴ and Z⁵, m, n, R¹, R², R³ and R⁴ are as defined informula (I), and Y is OH or NH₂ in which Z¹-Z⁵′ are Z¹-Z⁵ or groupsconvertible thereto, R¹′, R²′, R³′ and R⁴′ are R¹, R², R³ and R⁴ orgroups convertible thereto, and thereafter optionally or as necessaryconverting Z¹′-Z⁵′ to Z¹-Z⁵, converting R¹′, R²′, R³′ and R⁴′ to R¹, R²,R³ and R⁴, interconverting R¹, R², R³ and/or R⁴ and forming apharmaceutically acceptable derivative thereof.

The reaction of the compounds of formulae (IV) and (V) is a standardurea or carbamate formation reaction conducted by methods well known tothose skilled in the art (for example see March, J; Advanced OrganicChemistry, Edition 3 (John Wiley and Sons, 1985)). The process ispreferably carried out in a polar, non-nucleophilic solvent such asN,N-dimethylformamide.

R¹′, R²′, R³′ and R⁴′ are preferably R¹, R², R³ and R⁴. R¹′ ispreferably methoxy. R²′ is preferably hydrogen. R³′ is preferably R³such as hydrogen, vinyl or a carboxy ester-containing group. R⁴′ ispreferably H or a protecting group.

Conversions of R¹′, R²′, R³′ and R⁴′ and interconversions of R¹, R², R³and R⁴ are conventional. In compounds which contain an optionallysubstituted hydroxy group, suitable conventional hydroxy protectinggroups which may be removed without disrupting the remainder of themolecule include acyl and alkylsilyl groups.

For example R¹′ methoxy is convertible to R¹′ hydroxy by treatment withlithium and diphenylphosphine (general method described in Ireland et.al. (1973) J.Amer.Chem.Soc.,7829) or HBr. Alkylation of the hydroxygroup with a suitable alkyl derivative bearing a leaving group such ashalide and a protected amino, piperidyl, amidino or guanidino group orgroup convertible thereto, yields, after conversion/deprotection, R¹(C₁₋₆)alkoxy substituted by optionally N-substituted amino, piperidyl,guanidino or amidino.

Examples of Z¹′-Z⁵′ are CR^(1a)′ where R^(1a)′ is a group convertible toR^(1a).

R³′ alkenyl is convertible to hydroxyalkyl by hydroboration using asuitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation andreduction or oxymercuration.

R³′ carboxylate groups may be converted to R³ hydroxymethyl by reductionwith a suitable reducing agent such as lithium aluminium hydride.

R³ 1,2-dihydroxy can be prepared from R³′ alkenyl using osmium tetroxideor other reagents well known to those skilled in the art (see AdvancedOrganic Chemistry (Ed. March, J.) (John Wiley and Sons. 1985), p 732-737and refs. cited therein) or epoxidation followed by hydrolysis (seeAdvanced Organic Chemistry (Ed. March, J.) (John Wiley and Sons, 1985),p 332,333 and refs. cited therein).

R³ vinyl can be chain extended by standard homologation e.g byconversion to hydroxyethyl followed by oxidation to the aldehyde whichis then subjected to a Wittig reaction.

Compounds of formula (I) where R² and R³ are a divalent residue ═CR⁵ ¹R⁶ ¹ can be prepared by treatment of a compound of formula (I) where R³is alken-1-yl with a strong base in an aprotic solvent. Suitable basesinclude Ph₂PLi/PhLi (as described in Ireland et. al., J. Amer. Chem.Soc. (1973), 7829), t-BuLi, and suitable solvents include THF and ether.

Substituents on R³ alkyl or alkenyl may be interconverted byconventional methods, for example hydroxy may be derivatised byesterification, acylation or etherification. Hydroxy groups may beconverted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino,aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonylby conversion to a leaving group and substitution by the required groupor oxidation as appropriate or reaction with an activated acid,isocyanate or alkoxyisocyanate. Primary and secondary hydroxy groups canbe oxidised to an aldehyde or ketone respectively and alkyated with asuitable agent such as an organometallic reagent to give a secondary ortertiary alcohol as appropriate.

NH is converted to NR⁴ by conventional means such as alkylation with analkyl halide in the presence of base, acylation/reduction or reductivealkylation with an aldehyde.

It will be appreciated that under certain circumstances interconvertionsmay interfere, for example, the piperidine NH will require protection asan acyl derivative R⁴′, during coupling of the compounds of formulae(IV) and (V) and during conversion of R¹′, R²′ or R³′.

Compounds of formulae (IV) and (V) are known compounds) or preparedanalogously.

The isocyanate of formula (IV) may be prepared conventionally. A 4-aminoderivative such as 4-amino-quinoline, and phosgene, or phosgeneequivalent (eg triphosgene) provide the isocyanate or it may be preparedmore conveniently from a 4-carboxylic acid by a ‘one-pot’ CurtiusReaction with diphenyl phosphoryl azide (DPPA) [see T. Shiori et al.Chem. Pharm. Bull. 35, 2698-2704 (1987)].

The 4-carboxy derivatives are commercially available or may be preparedby conventional procedures for preparation of carboxy heteroaromaticswell known to those skilled in the art. For example, quinazolines may beprepared by standard routes as described by T. A. Williamson inHeterocyclic Compounds, 6, 324 (1957) Ed. R. C. Elderfield. Pyridazinesmay be prepared by routes analogous to those described in ComprehensiveHeterocyclic Chemistry, Volume 3, Ed A. J. Boulton and A. McKillop andnapthyridines may be prepared by routes analogous to those described inComprehensive Heterocyclic Chemistry, Volume 2, Ed A. J. Boulton and A.McKillop.

The 4-amino derivatives are commercially available or may be prepared byconventional procedures from a corresponding 4-chloro derivative bytreatment with ammonia (O. G. Backeberg et. al., J. Chem Soc., 381,1942.) or propylamine hydrochloride (R. Radinov et. al., Synthesis, 886,1986).

A 4-chloroquinoline is prepared from the corresponding quinolin-4-one byreaction with phosphorus oxychloride (POCl₃) or phosphoruspentachloride, PCl₅.

A 4-chloroquinazoline is prepared from the correspondingquinazolin-4-one by reaction with phosphorus oxychloride (POCl₃) orphosphorus pentachloride, PCl₅. A quinazolinone and quinazolines may beprepared by standard routes as described by T. A. Williamson inHeterocyclic Compounds, 6, 324 (1957) Ed. R. C. Elderfield. Pyridazinesmay be prepared by routes analogous to those described in ComprehensiveHeterocyclic Chemistry, Volume 3, Ed A. J. Boulton and A. McKillop andnapthyridines may be prepared by routes analogous to those described inComprehensive Heterocyclic Chemistry, Volume 2, Ed A. J. Boulton and A.McKillop.

4-Hydroxy-1,5-naphthyridines can be prepared from 3-aminopyridinederivatives by reaction with diethyl ethoxymethylene malonate to producethe 4-hydroxy-3-carboxylic acid ester derivative with subsequenthydrolysis to the acid, followed by thermal decarboxylation in quinoline(as for example described for 4-Hydroxy-[1,5]naphthyridine-3-carboxylicacid, Joe T. Adams et al., J.Amer.Chem.Soc., 1946, 68, 1317). A4-hydroxy-[1,5]naphthyridine can be converted to the 4-chloro derivativeby heating in phosphorus oxychloride. A 4-amino 1,5-naphthyridine can beobtained from the 4-chloro derivative by reaction with n-propylamine inpyridine.

Similarly, 6-methoxy-1,5-naphthyridine derivatives can be prepared from3-amino-6-methoxypyridine.

1,5-Naphthyridines may be prepared by other methods well known to thoseskilled in the art (for examples see P. A. Lowe in “ComprehensiveHeterocyclic Chemistry” Volume 2, p581-627, Ed A. R. Katritzky and C. W.Rees, Pergamon Press, Oxford, 1984).

The 4-hydroxy and 4-amino-cinnolines may be prepared following methodswell known to those skilled in the art [see A. R. Osborn and K.Schofield, J. Chem. Soc. 2100 (1955)]. For example, a2-aminoacetopheneone is diazotised with sodium nitrite and acid toproduce the 4-hydroxycinnoline with conversion to chloro and aminoderivatives as described for 1,5-naphthyridines.

For compounds of formula (V) where Y is NH₂ suitable amines may beprepared from the corresponding acid or alcohol (Y is CO₂H or CH₂OH). Ina first instance, an N-protected piperidine containing an acid bearingsubstituent, can undergo a Curtius rearrangement and the intermediateisocyanate can be converted to the amine by standard methods well knownto those skilled in the art. For example, an acid-substitutedN-protected piperidine can undergo a Curtius rearrangement e.g. ontreatment with diphenylphosphoryl azide and beating, and theintermediate isocyanate reacts in the presence of2-trimethylsilylethanol to give the trimethylsilylethylcarbamate (T. L.Capson & C. D. Poulter, Tetrahedron Letters, 1984, 25, 3515). Thisundergoes cleavage on treatment with tetrabutylammonium fluoride to givethe 4-amine-substituted N-protected piperidine.

In a second instance, an N-protected piperidine containing an alcoholbearing substituent undergoes a Mitsunobu reaction (for example asreviewed in Mitsunobu, Synthesis, (1981), 1), for example withsuccinimide in the presence of diethyl azodicarboxylate andtriphenylphosphine to give the phthalimidoethylpiperidine. Removal ofthe phthaloyl group, for example by treatment with methylhydrazine,gives the amine of formula (V).

Compounds of formula (V) where n=1 or 2 may be prepared from thecompound where n=0 by homologation eg starting from a compound offormula (V) where Y═CO₂H.

Where R₃ and R₄ form a group such as —(CH₂)₄—, the azabicylicintermediate of formula (V) may be prepared from the ketone such as1-aza-8-(equatorial)-formyloxy-bicyclo[4,4,0]decan-2-one. This ketonemay be prepared by a literature procedure [H. E. Schoemaker et al.Tetrahedron, 34, 163-172 (1978)] and hydrolysed to the 8-alcohol withsodium hydroxide. The alcohol may then subjected to a Mitsunobu reaction(diethylazodicarboxylate/triphenyl phosphine) [eg. see K. Y. Ko et al.J. Org. Chem. 51, 5353 (1986)]) in the presence of benzoic acid toafford the 8-axial benzoate, which can be hydrolysed with sodiumhydroxide in aqueous dioxan to the axial 8-hydroxy-derivative. Thehydroxyl may be protected with a trimethylsilyl group and then reactedwith LDA (lithium diisopropylamide) and an alkylating agent such as ahaloalkane derivative e.g. 1-bromopropane, to give the 3-alkylderivative (mixture of axial/equatorial isomers at C-3). Reduction ofthe lactam moiety with lithium aluminium hydride gives the required8-(ax)-hydroxy-bicyclodecane. Homologous compounds where n=1 or 2 may beprepared by conventional homologation routes, for example by Wittigreaction of the above bicyclic ketone followed by reduction of thealkylene product.

Conversions of R¹′, R²′, R³′ and R⁴′ may be carried out on theintermediates of formulae (IV) and (V) prior to their reaction toproduce compounds of formula (1) in the same way as described above forconversions after their reaction.

Where a trans-substituted compound of formula (I) is required, atrans-substituted piperidine moiety of formula (V) may be prepared fromthe corresponding cis isomer of formula (V) having an R³′ vinyl group inthe 3-position with a substituent that can subsequently be converted tothe required group (CH₂)_(n)Y by heating in formaldehyde.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The antibiotic compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibiotics.

The composition may be formulated for administration by any route, suchas oral, topical or parenteral. The compositions may be in the form oftablets, capsules, powders, granules, lozenges, creams or liquidpreparations, such as oral or sterile parenteral solutions orsuspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

No toxicological effects are indicated when a compound of formula (I) ora pharmaceutically acceptable salt or in vivo hydrolysable ester thereofis administered in the above-mentioned dosage range.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with other antibiotics orwith a β-lactamase inhibitor may be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms.

EXAMPLE 11-Aza-8-(ax)-[(6-methoxyquinolin-4-yl)-aminocarbonyloxy]-3-(ax)-n-pentyl-bicyclo[4,4,0]decane

(a) 1-Aza-3-n-pentyl-8-(ax)-hydroxy-bicyclo[4,4,0]decan-2-one

A 1.5 M solution of lithium dilsopropylamide in cyclohexane (2.25 ml)was added to a solution of1-aza-8-(ax)-(trimethylsilyloxy)-bicyclo[4,4,0]decan-2-one (0.73 g)(King et al., Bioorg Med Chem Letts., vol.2, p.1147 (1992)) in drytetrahydrofuran (10 ml) at −78° C. and the solution was stirred for 10minutes. 1-Bromopropane (0.503 g) was added and the solution was stirredat −78° C. for 1 hour and allowed to warm up to room temperatureovernight. The mixture was basified with aqueous sodium bicarbonatesolution and evaporated to dryness. It was re-suspended in 1:1tetrahydrofuran-water (100 ml), acidified to pH 2 with 2 M hydrochloricacid, and stirred at room temperature for 30 minutes. The mixture wasbasified with 10% sodium carbonate solution, evaporated to dryness,treated with chloroform, dried over sodium sulfate and evaporated toafford an oil.

MS (+ve ion electrospray) m/z 240 (MH+)

(b) 1-Aza-3-n-pentyl-8-(ax)-hydroxy-bicyclo[4,4,0]decane

A solution of 1-aza-3-n-pentyl-8-(ax)-hydroxy-bicyclo[4,4,0]decan-2-one(0.3 g) in dry tetrahydrofuran (5 ml) was treated with lithium aluminiumhydride (0.10 g) and the mixture was heated under reflux for 3 hours.The cooled solution was treated dropwise with a solution of 2M sodiumhydroxide until a white precipitate had formed. Dichloromethane andanhydrous sodium sulfate were added and the solution was filtered andevaporated to dryness to give an oil (0.26 g).

MS (+ve ion electrospray) m/z 226 (MH+)

(c) Title Compound

A suspension of 6-methoxyquinoline-4-carboxylic acid (0.142 g) indichloroethane (3 ml) was treated with triethylamine (71 mg) followed bydiphenylphosphoryl azide (0.193 g) and the mixture was stirred at roomtemperature for 1.5 hours. The resultant solution was heated (oil bathtemperature 100° C.) for 0.5 hours to form the isocyanate. A solution of1-aza-3-n-pentyl-8-(ax)-hydroxy-bicyclo[4,4,0]decane (0.125 g) indichloroethane (1 ml) was added and the solution was heated under refluxfor 4 hours. A further batch of isocyanate [(prepared from6-methoxyquinoline-4-carboxylic acid (47 mg)] in dichloroethane wasadded and the solution heated under reflux for a further 1 hour, left atroom temperature overnight, and evaporated to dryness. The product wasdissolved in tetrahydrofuran and basified with aqueous sodium hydroxide,evaporated to dryness, and partitioned between water and chloroform. Theorganic fraction was dried over sodium sulfate, evaporated andchromatographed on silica gel in ethyl acetate-hexane (1:2) to affordthe title compound as a white solid (40 mg), after trituration withether-hexane.

MS (+ve ion electrospray) m/z 426 (MH+).

EXAMPLE 21-Aza-8-(ax)-[(6-methoxyquinolin-4-yl)aminocarbonyloxy]-3-(eq)-n-pentyl-bicyclo[4,4,0]decane

Reaction of 6-methoxyquinoline-4-isocyanate prepared from6-methoxyquinoline4-carboxylic acid (0.142 g) with1-aza-3-n-pentyl-8-(ax)-hydroxy-bicyclo[4,4,0]decane (0.10 g) (by theMethod of Example 1(c)) and chromatography of the product on silica gelin ethyl acetate-hexane (1:1) gave the compound of Example 1 (30 mg).Continued elution with ethyl acetate, followed by preparative TLC[methanol-ethyl acetate (1:10)] gave the title compound as a pale yellowfoam (14 mg).

MS (+ve ion electrospray) m/z 426 (MH+).

EXAMPLE 31-Heptyl-4-[N-(6-methoxyquinolin-4-yl)aminocarbonyloxy]piperidine

(a) 1-Heptyl-4-hydroxypiperidine

4-Hydroxypiperidine was dissolved in N,N-dimethylformamide (20 ml) andtreated with potassium carbonate (1.5 g, 10.8 mmol) and 1-iodoheptane(1.8 ml, 11.3 mmol). After stirring for 2 h the mixture was diluted withethyl acetate, washed with water, brine, dried and evaporated.

(b) Title Compound

6-Methoxyquinoline-4-isocyanate was prepared from the correspondingcarboxylic acid (1 g, 4.9 mmol) by the method of Example 1(c).1-Heptyl-4-hydoxypiperidine (1.0 g, 5.0 mmol) was added and the mixturestirred for 2.5 h. After washing with sodium carbonate and brine thesolution was dried and evaporated and the product purified on silica geleluting with methanol-ethyl acetate (5:95), MH⁺ 400.

EXAMPLE 4 1-Heptyl-4-(6-methoxyquinolin4-yl)ureidopiperidine

(a) 1-Benzyl-4-(6-methoxyquinolin-4-yl)ureidopiperidine

6-Methoxyquinoline-4-isocyanate was prepared from the correspondingcarboxylic acid (1 g, 4.9 mmd) by the method of Example 1(c) and4-amino-1-benzyl piperidine (1.0 ml, 5.0 mmol) was added. After stirringfor 3 h the mixture was diluted with dichloromethane, washed with sodiumcarbonate solution, brine, dried and evaporated. Purification on silicagel eluting with methanol-ethyl acetate mixtures gave a yellow solid(0.51 g, 27%) MH⁺ 391.

(b) Title Compound

The product from Example 4(a) (0.50 g, 1.28 mmol) in methanol (25 ml)was hydrogenated over 10% palladium on charcoal (0.30 g) for 4 days. Themixture was filtered through celite and evaporated. The residue wasdissolved in N,N-dimethylformamide (10 ml) and treated with1-iodoheptane (0.24 ml, 1.5 mmol) and potassium carbonate (0.21 g, 1.5mmol). After stirring for 18 h the mixture was diluted with ethylacetate, washed with water, brine, dried and evaporated. Purification onsilica gel eluting with methanol-chloroform-ammonia (5:95:0.5) gave ayellow solid (0.27 g, 55%), MH⁺ 399.

EXAMPLE 5N-(cis-1-Heptyl-3-(R/S)-hydroxymethyl-4-(S/R)-piperidyl)-N′-(6-methoxyquinolin-4-yl)ureaoxalate

(a)4-Benzylamino-1-tert-butoxycarbonyl-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridine

A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-one(prepared from 3-ethoxycarbonylpiperidin-4-one anddi-tert-butyl-dicarbonate in dichloromethane and triethylamine) (25 g)and benzylamine (10.85 g) in toluene was heated under reflux in a Deanand Stark apparatus for 18 hours and then evaporated to dryness to givean oil.

(b)cis-4-(S/R)-Benzylamino-1-tert-butoxycarbonyl-3-(R/S)-ethoxycarbonylpiperidine

The enamine (5a) (25 g) in ethanol (300 ml) was hydrogenated overplatinum oxide (1.5 g) for 4 days, filtered, and evaporated to dryness.It was chromatographed on silica gel (ethyl acetate-hexane) to affordthe title compound as an oil.

MS (+ve ion electrospray) m/z 363 (MH+).

(c)cis-4-(S/R)-Amino-1-tert-butoxycarbonyl-3-(R/S)-ethoxycarbonylpiperidine

The amine (5b) (4 g) in ethanol (80 ml) containing acetic acid (0.73 g)was hydrogenated at 50 psi (Parr reaction vessel) over 10%palladium-carbon (10 g) for 18 hours, filtered and evaporated to drynessto afford the acetate salt of the title compound as a white solid (3 g).

MS (+ve ion electrospray) m/z 273 (MH+).

It was converted to the oily free base by extraction usingdichloromethane-sodium carbonate and drying over sodium sulfate.

(d)N-(cis-1-tert-Butoxycarbonyl-3-(R/S)-ethoxycarbonyl-4-(S/R)-piperidyl)-N′-(6-methoxyquinolin-4-yl)urea

A suspension of 6-methoxyquinoline-4-carboxylic acid (0.98 g) in drytoluene (50 ml) was treated with triethylamine (1.95 g) followed bydiphenylphosphoryl azide (1.39 g) and the mixture was stirred at roomtemperature for 8 hours. The resultant solution was treated with theamine (5c) and then heated under reflux for 4 hours and evaporated todryness. The product was chromatographed on silica gel (ethylacetate-hexane) to afford the title compound (1.98 g) as a foam.

MS (+ve ion electrospray) m/z 473 (MH+).

(e)N-(cis-3-(R/S)-Ethoxycarbonyl-4-(S/R)-piperidyl)-N′-(6-methoxyquinolin-4-yl)urea

The urea (5d) (1.0 g) was treated with dichloromethane (30 ml) andtrifluoroacetic acid (20 ml) at room temperature for 3 hours andevaporated to dryness. It was basified with sodium carbonate solutionand evaporated to dryness. The solid was extracted three times withethanol-chloroform (1:9) and evaporated to dryness to afford a foam(0.75 g).

MS (+ve ion electrospray) m/z 373 (MH+).

(f)N-(cis-3-(R/S)-Ethoxycarbonyl-1-heptyl-4-(S/R)-piperidyl)-N′-(6-methoxyquinolin-4-yl)ureaoxalate

The amine (5e) (0.75 g) in dry ethanol (15 ml) was treated withheptaldehyde (0.636 g) and sodium triacetoxyborohydride (0.459 g) for 1hour at room temperature. Sodium bicarbonate solution was added and themixture was extracted with dichloromethane, dried over sodium sulfate,and evaporated to afford an oil. Chromatography on silica gel (ethylacetate-hexane) gave the title compound (0.68 g) as an oil.

MS (+ve ion electrospray) m/z 471 (MH+).

The free base in dichloromethane was treated with 1 molar equivalent ofoxalic acid in ether and the resulting solid was collected, trituratedwith ether, to afford the oxalate salt as a white solid.

(g) Title Compound

The ester (5f) (0.12 g) in dry tetrahydrofuran (4 ml) at 0° C. wastreated with lithium aluminium hydride (0.655 ml of a 1M solution inether) for 5 hours, and at room temperature for 1 hour, then it wasquenched by the addition of 2M sodium hydroxide. Dichloromethane andsodium sulfate were added and the solution was filtered and evaporatedto dryness. The product was chromatographed on silica gel(methanol-dichloromethane) to afford the title compound (0.055 g), asthe oily free base.

MS (+ve ion electrospray) m/z 429 (MH+).

The free base in dichloromethane was converted to the oxalate salt inthe normal manner, affording a white solid.

EXAMPLE 6N-(cis-1-Heptyl-3-(R/S)-hydroxymethyl-4-(S/R)-piperidyl)-N′-(6-methoxy-[1,5]-naphthyridin-4-yl)ureaOxalate

(a) 4-Hydroxy-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid Ethyl Ester

3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate(20.2 ml) in Dowtherm A (400 ml) were heated at reflux. under argon for1 hour. The cooled reaction mixture was poured into pentane (1 litre).The precipitated solid was collected by filtration, washed with pentaneand dried to afforded a solid (24.78 g, crude).

(b) 4-Hydroxy-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid

The ester (6a) (0.642 g) in 10% aqueous sodium hydroxide (115 ml) washeated at reflux for 1.5 hours. The reaction mixture was cooled thenacidified with glacial acetic acid. The precipitated solid was collectedby filtration, washed with water and dried in vacuo to afford a beigesolid (0.542 g).

MS (+ve ion electrospray) m/z 221 (MH⁺).

(c) 4-Chloro-6-methoxy-[1,5]naphthyridine

The acid (6b) (6.82 g) was heated in quinoline (20 ml) at reflux for 2hours, the mixture was cooled and poured into ether (200 ml) and theorange solid was filtered and washed with ether (5×200 ml). A sample(3.87 g) of the dried solid was treated with phosphorus oxychloride (30ml) at room temp for 3 hours, the solvent was removed in vacuo and theresidue quenched with crushed ice (200 g). The mixture was basified withammonia solution and filtered. The solid was washed with dichloromethane(10×100 ml), which was evaporated and chromatographed on silica gel(dichloromethane as eluent) to give a yellow solid (3.0 g).

MS (+ve ion electrospray) m/z 195, 197 (MH⁺).

(d) 4-Amino-6-methoxy-[1,5]naphthyridine

A solution of the chloro compound (6c) (2.0 g) in pyridine (30 ml) wastreated with n-propylamine hydrochloride (6.0 g) and the mixture heatedat reflux for 16 hours. The reaction mixture was cooled and partitionedbetween water and ethyl acetate. The aqueous phase was washed with ethylacetate, the combined organics dried (Na₂SO₄) and the solvent removedunder reduced pressure. Purification by chromatography on silica gel(5-10% methanol in dichloromethane) afforded a yellow solid (1.0 g).

¹H NMR (CDCl₃) δ: 4.05 (3H, s), 5.36 (2H, bs), 6.71 (1H, d, J=5 Hz),7.08 (1H, d, J=9 Hz), 8.10 (1H, d, J=9 Hz), 8.40 (1H, d, J=5 Hz).

MS (+ve ion electrospray) m/z: 176 (MH⁺).

(e)N-(cis-1-tert-Butoxycarbonyl-3-(R/S)-ethoxycarbonyl-4-(S/R)-piperidyl)-N′-(6-methoxy-[1,5]-naphthyridin-4-yl)urea

To a solution of amine (6d) (0.5 g) in chloroform (4 ml) was added1,1′-carbonyldiimidazole (0.76 g) and dimethylaminopyridine (0.38 g) andthe solution was stirred at room temperature for 3.5 hours andevaporated to dryness. The product was heated at 100° C. in dry DMF (7ml) containing the amine (5c) (0.85 g,), for 3 hours. Aqueous sodiumcarbonate was added and the mixture was extracted with dichloromethane,dried over sodium sulfate, and evaporated to afford a foam.Chromatography on silica gel (ethyl acetate-hexane) gave an oil (0.928g).

MS (+ve ion electrospray) m/z 474 (MH+).

(f)N-(cis-3-(R/S)-Ethoxycarbonyl-4-(S/R)-piperidyl)-N′-(6-methoxy-[1,5]-naphthyridine-4-yl)urea

The urea (6e) (0.92 g) was treated with dichloromethane (20 ml) andtrifluoroacetic acid (30 ml) at room temperature for 3 hours andevaporated to dryness. It was basified with sodium carbonate solutionand evaporated to dryness. The solid was extracted three times with warmethanol-chloroform (1:9) and evaporated to dryness to afford a foam(0.80 g).

MS (+ve ion electrospray) m/z 374 (MH+).

(g)N-(cis-3-(R/S)-Ethoxycarbonyl-1-heptyl-4-(S/R)-piperidyl)-N′-(6-methoxy-[1,5]-naphthyridin-4-yl)ureaoxalate

The amine (6f) (0.80 g) in dry ethanol (20 ml) was treated withheptaldehyde (0.26 g) and sodium triacetoxyborohydride (0.82 g) for 1hour at room temperature. Sodium bicarbonate solution was added and themixture was extracted with dichloromethane, dried over sodium sulfate,and evaporated to afford an oil. Chromatography on silica gel (ethylacetate-hexane) gave the title compound (0.72 g) as an oil.

MS (+ve ion electrospray) m/z 472 (MH+).

The free base in dichloromethane was treated with 1 molar equivalent ofoxalic acid in ether and the resulting solid was collected, trituratedwith ether, to afford the oxalate salt as a white solid.

(h) Title Compound

The ester (6 g) (0.10 g) in dry tetrahydrofuran (7 ml) was treated withlithium aluminium hydride (0.42 ml of a 1M solution in ether) at 0° C.for 1.5 hours and at room temperature for 2 hours, then it was quenchedby the addition of 2M sodium hydroxide. Dichloromethane and sodiumsulfate were added and the solution was filtered and evaporated todryness. The product was chromatographed on silica gel(methanol-dichloromethane) to afford the title compound (0.074 g), asthe oily free base.

MS (+ve ion electrospray) m/z 430(MH+). ¹H NMR (CDCl₃) δ: 0.88 (3H, t),1.20 (9H, bs), 1.40 (2H, bs), 1.9-2.4 (6H, m), 2.50 (1H, bd), 2.90 (2H,m), 3.90 (2H, m), 4.10 (3H, s), 4.17 (1H, m) 6.60 (1H, bd), 7.10 (1H,d), 8.20 (1H, d), 8.38 (1H, d), 8.61 (1H, d), 8.78 (1H, s).

The free base in dichloromethane was converted to the oxalate salt inthe normal manner. affording a white solid.

EXAMPLE 7N-(1-Heptyl-4-piperidyl-N′-(6-methoxy-1,5-naphthyridin-4-yl)urea Oxalate

A solution of the amine (6d) (0.08, 0.5 mmol) in chloroform (2 ml) wastreated with N,N-dimethylaminopyridine (0.06 g, 0.5 mmol) then1,1′-carbonyldiimidazole (0.11 g, 0.7 mmol). After 2 hours thechloroform was removed by evaporation and the residue treated with asolution of 4-amino-1-heptylpiperidine (0.1 g, 0.5 mmol) inN,N-dimethylformamide (1 ml) and the mixture heated to 100° C. for 1hour. Water (2 ml) was added dropwise and filtration gave a white solid.Chromatography on silica eluting with a methanol in ethyl acetategradient afforded the title compound as a white solid, (0.1 g, 50%).

¹H NMR (CD₃OD) 0.80 (3H, t), 1.20 (8H, m), 1.50 (4H, m), 1.90 (2H, m),2.10 (2H, m), 2.25 (2H, m), 2.85 (2H, m), 3.55(1H,m), 4.00 (3H, s), 7.10(1H, d), 8.00 (1H, d), 8.20 (1H, d), 8.35 (1H, d).

The following example was prepared by procedures analogous to thosedescribed herein:

EXAMPLE 81-Aza-8-(ax)-[(6-methoxyquinolin-4yl)-aminocarbonyloxy]-3-(ex)-n-hexyl-bicyclo[4,4,0]decane

Biological Activity

The MIC (μg/ml) of compounds 1, 3 and 4 against various organisms wasdetermined.

Examples 1, 5, 6 and 7 have an MIC of less than or equal to 1 μg/mlagainst one or more of a range of gram positive and gram negativebacteria.

The remaining compounds 2, 3, 4 and 8 showed an MIC of less than orequal to 16 μ/ml against one or more of a range of gram positive andgram negative bacteria. (See table 1).

TABLE 1 Exam- Exam- Exam- Exam- Exam- Exam- Organism ple 1 ple 3 ple 4ple 5 ple 6 ple 7 S. aureus 2 8 16  1   0.5 1 Oxford S. aureus 4 4 8 1 11 WCUH29 S. aureus 8 8 16  ND ND ND Carter 37 E. faecalis I 8 8 8 4 8 8M. catarrhalis 32 16 ND ND ND ND Ravasio S. pneumoniae 1 4 2 ND ND ND R6

What is claimed is:
 1. A compound of formula (I):

wherein: one of Z¹, Z², Z³, Z⁴ and Z⁵ is CR^(1a) and the remainder areCH, or one of Z¹, Z², and Z³ is N and the remainder are CH; R¹ isselected from hydroxy; (C₁₋₆) alkoxy optionally substituted by(C₁₋₆)alkoxy, amino, piperidyl, guanidino or amidino optionallyN-substituted by one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonylgroups, NH₂CO, hydroxy, thiol, (C₁₋₆)alkylthio, heterocyclylthio,heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkoxy-substituted (C₁₋₆)alkyl; halogen;(C₁₋₆)alkyl; (C₁₋₆)alkylthio; nitro; trifluoromethyl; azido; acyl;acyloxy; acylthio; (C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide;arylsulphonyl; arylsulphoxide or an amino, piperdyl, guanidino oramidino group optionally N-substituted by one or two (C₁₋₆)alkyl, acylor (C₁₋₆)alkylsulphonyl groups, wherein acyl is selected from(C₁₋₆)alkoxycarbonyl, formyl and (C₁₋₆)alkylcarbonyl, or when one of Z¹,Z², and Z³ is N, R¹ may instead be hydrogen; R^(1a) is selected fromhydrogen and the groups listed above for R¹; either R² is hydrogen; andR³ is in the 2- or 3-position and is hydrogen or (C₁₋₆)alkyl or(C₂₋₆)alkenyl optionally substituted with 1 to 3 groups selected from:thiol; halogen; (C₁₋₆)alkylthio; trifluoromethyl; azido;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;(C₂₋₆)alkenylcarbonyl; hydroxy optionally substituted by (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl or aminocarbonyl whereinthe amino group is optionally substituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkylcarbonyl or (C₂₋₆)alkenylcarbonyl; amino optionally mono- ordisubstituted by (C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl,(C₂₋₆)alkenyloxycarbonyl, (C₂₋₆)alkenylcarbonyl, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₁₋₆)alkylsulphonyl, (C₂₋₆)alkenylsulphonyl oraminocarbonyl wherein the amino group is optionally substituted by(C₁₋₆)alkyl or (C₂₋₆)alkenyl; aminocarbonyl wherein the amino group isoptionally mono- or disubstituted by (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₁₋₆)alkoxycarbonyl, (C₁₋₆)alkylcarbonyl, (C₂₋₆)alkenyloxycarbonyl or(C₂₋₆)alkenylcarbonyl; oxo; (C₁₋₆)alkylsulphonyl;(C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the amino groupis optionally substituted by (C₁₋₆)alkyl or (C₂₋₆)alkenyl; or when R³ isin the 2-position it may with R⁴ form a C₃₋₅ alkylene group optionallysubstituted by a group R⁵ selected from: (C₃₋₁₂)alkyl;hydroxy(C₃₋₁₂)alkyl; (C₁₋₁₂)alkoxy(C₃₋₁₂)alkyl;(C₁₋₁₂)alkanoyloxy(C₃₋₁₂)alkyl; (C₃₋₆)cycloalkyl(C₃₋₁₂)alkyl; hydroxy-,(C₁₋₁₂)alkoxy- or (C₁₋₁₂)alkanoyloxy-(C₃₋₆)cycloalkyl(C₃₋₁₂)alkyl;cyano(C₃₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; tetrahydrofuryl;mono- or di-(C₁₋₁₂)alkylamino(C₃₋₁₂)alkyl; acylamino(C₃₋₁₂)alkyl;(C₁₋₁₂)alkyl- or acylaminocarbonyl(C₃₋₁₂)alkyl; mono- or di-(C₁₋₁₂)alkylamino(hydroxy)(C₃₋₁₂)alkyl; optionally substitutedphenyl(C₁₋₂)alkyl, phenoxy(C₁₋₂)alkyl or phenyl(hydroxy)(C₁₋₂)alkyl;optionally substituted diphenyl(C₁₋₂)alkyl; optionally substitutedphenyl(C₂₋₃)alkenyl; optionally substituted benzoyl or benzoylmethyl;optionally substituted heteroaryl(C₁₋₂)alkyl; and optionally substitutedheteroaroyl or heteroaroylmethyl, wherein acyl is selected from(C₁₋₆)alkoxycarbonyl, formyl and (C₁₋₆)alkylcarbonyl; or R³ is in the3-position and R² and R³ together are a divalent residue ═CR⁵ ¹ R⁶ ¹where R⁵ ¹ and R⁶ ¹ are independently selected from H, (C₁₋₆)alkyl,(C₂₋₆)alkenyl, aryl(C₁₋₆)alkyl and aryl(C₂₋₆)alkenyl, any alkyl oralkenyl moiety being optionally substituted by 1 to 3 groups selectedfrom those listed above for substituents on R³; R⁴ forms a group with R³as above defined or is a group —CH₂—R⁵ in which R⁵ is as defined above;n is 0, 1 or 2; and A is NHC(O)NH or NHC(O)O; an N-oxide of a compoundof formula (I), or a pharmaceutically acceptable salt of a compound offormula (I) or its N-oxide.
 2. A compound according to claim 1 whereinZ¹-Z⁵ are each CH or Z¹ is N and Z²-Z⁵ are each CH.
 3. A compoundaccording to claim 1 wherein R¹ is methoxy, amino(C₃₋₅)alkyloxy,guanidino(C₃₋₅)alkyloxy, nitro or fluoro.
 4. A compound according toclaim 1 wherein A is NHCONH and n is
 0. 5. A compound according to claim1 wherein R³ is in the 3-position and is hydroxy(C₁₋₆)alkyl or1,2-dihydroxy(C₂₋₆)alkyl optionally substituted on the hydroxy group(s).6. A compound according to claim 1 wherein R⁴ is (C₅₋₁₀)alkyl,unsubstituted phenyl(C₂₋₃)alkyl or unsubstituted phenyl(C₃₋₄)alkenyl. 7.A compound according to claim 1 selected from:1-aza-8-(ax)-[(6-methoxyquinolin-4-yl)-aminocarbonyloxy]-3-(ax)-n-pentyl-bicyclo[4,4,0]decane;1-aza-8-(ax)-[(6-methoxyquinolin-4-yl)-aminocarbonyloxy]-3-(eq)-n-pentyl-bicyclo[4,4,0]decane;1-heptyl-4-[N-(6-methoxyquinolin-4-yl)aminocarbonyloxy]piperidine;1-heptyl-4-(6-methoxyquinolin-4-yl)ureidopiperidine;N-(cis-1-heptyl-3-(R/S)-hydroxymethyl-4-(S/R)-piperidyl)-N′-(6-methoxyquinolin-4-yl)urea;N-(cis-1-heptyl-3-(R/S)-hydroxymethyl-4-(S/R)-piperidyl)-N′-(6-methoxy-[1,5]-naphthyridin-4-yl)urea;N-(1-heptyl-4-piperidyl-N′-(6-methoxy-1,5-naphthyridin-4-yl)urea;1-aza-8-(ax)-[(6-methoxyquinolin-4-yl)-aminocarbonyloxy]-3-(ex)-n-hexyl-bicyclo[4,4,0]decane;an N-oxide of any of the foregoing compounds, or a pharmaceuticallyacceptable salt of any of the foregoing compounds or an N-oxide thereof.8. A process for preparing a compound of formula (I), an N-oxide of acompound of formula (I), or a pharmaceutically acceptable salt of acompound of formula (I) or its N-oxide according to claim 1, whichprocess comprises reacting a compound of formula (IV) with a compound offormula (V):

wherein Y is OH or NH₂, Z¹′-Z⁵′ are, respectively, Z¹-Z⁵ or groupsconvertible thereto, R¹′, R²′, R³′ and R⁴′ are, respectively, R¹, R², R³and R⁴ or groups convertible thereto, and Z¹, Z², Z³, Z⁴, Z⁵, m, n, R¹,R², R³ and R⁴ are as defined in formula (I), and thereafter optionallyor as necessary converting Z¹′-Z⁵′ to Z¹-Z⁵, converting R¹′, R²′, R³′and R⁴′ to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and/or R⁴ andforming an N-oxide thereof, or a pharmaceutically acceptable saltthereof or its N-oxide.
 9. A pharmaceutical composition comprising acompound of formula (I), an N-oxide of a compound of formula (I), or apharmaceutically acceptable salt of a compound of formula (I) or itsN-oxide according to claim 1, and a pharmaceutically acceptable carrier.10. A method of treatment of bacterial infections in mammals, whichmethod comprises the administration to a mammal in need of suchtreatment of an effective amount of a compound of formula (I), anN-oxide of a compound of formula (I), or a pharmaceutically acceptablesalt of a compound of formula (I) or its N-oxide according to claim 1.11. A method according to claim 10, wherein said mammal is a human. 12.A compound according to claim 2 wherein R¹ is methoxy,amino(C₃₋₅)alkyloxy, guanidino(C₃₋₅)alkyloxy, nitro or fluoro.
 13. Acompound according to claim 2 wherein A is NHCONH and n is
 0. 14. Acompound according to claim 2 wherein R³ is in the 3-position and ishydroxy(C₁₋₁₆)alkyl or 1,2-dihydroxy(C₂₋₆)alkyl optionally substitutedon the hydroxy group(s).
 15. A compound according to claim 2 wherein R⁴is (C₅₋₁₀)alkyl, unsubstituted phenyl(C₂₋₃)alkyl or unsubstitutedphenyl(C₃₋₄)alkenyl.
 16. A compound according to claim 12 wherein A isNHCONH and n is 0, R³ is in the 3-position and is hydroxy(C₁₋₆)alkyl or1,2-dihydroxy(C₂₋₆)alkyl optionally substituted on the hydroxy group(s),and R⁴ is (C₅₋₁₀)alkyl, unsubstituted phenyl(C₂₋₃)alkyl or unsubstitutedphenyl(C₃₋₄)alkenyl.